Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence

Mohammed Mamdani, Vernell Williamson, Gowon O. McMichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D. Van Der Vaart, Bradley Todd Web, Silviu Alin Bacanu, Gursharan Kalsi, Kenneth S. Kendler, Michael F. Miles, Danielle Dick, Brien P. Riley, Catherine Dumur, Vladimir I. Vladimirov, V. Hesselbrock, Howard EdenbergJohn Nurnberger, Tatiana Foroud, S. Kuperman, J. Kramer, B. Porjesz, L. Bierut, A. Goate, J. Rice, K. Bucholz, M. Schuckit, J. Tischfield, L. Almasy, R. Taylor, D. Dick, L. Bauer, D. Koller, Sean O'Connor, L. Wetherill, Xiaoling Xuei, Grace Chan, S. Kang, N. Manz, M. Rangaswamy, J. Rohrbaugh, J. C. Wang, A. Brooks, F. Aliev, A. Parsian, M. Reilly

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

Original languageEnglish (US)
Article numbere0137671
JournalPLoS One
Volume10
Issue number9
DOIs
StatePublished - Sep 18 2015

Fingerprint

Nucleus Accumbens
alcohol abuse
MicroRNAs
microRNA
Alcoholism
Genes
Alcohols
Gene Expression
Messenger RNA
genes
gene expression
genetic markers
genome
oxidative phosphorylation
astrocytes
neuroglia
Gene expression
transcriptome
Genome
signs and symptoms (animals and humans)

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mamdani, M., Williamson, V., McMichael, G. O., Blevins, T., Aliev, F., Adkins, A., ... Reilly, M. (2015). Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence. PLoS One, 10(9), [e0137671]. https://doi.org/10.1371/journal.pone.0137671

Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence. / Mamdani, Mohammed; Williamson, Vernell; McMichael, Gowon O.; Blevins, Tana; Aliev, Fazil; Adkins, Amy; Hack, Laura; Bigdeli, Tim; Van Der Vaart, Andrew D.; Web, Bradley Todd; Bacanu, Silviu Alin; Kalsi, Gursharan; Kendler, Kenneth S.; Miles, Michael F.; Dick, Danielle; Riley, Brien P.; Dumur, Catherine; Vladimirov, Vladimir I.; Hesselbrock, V.; Edenberg, Howard; Nurnberger, John; Foroud, Tatiana; Kuperman, S.; Kramer, J.; Porjesz, B.; Bierut, L.; Goate, A.; Rice, J.; Bucholz, K.; Schuckit, M.; Tischfield, J.; Almasy, L.; Taylor, R.; Dick, D.; Bauer, L.; Koller, D.; O'Connor, Sean; Wetherill, L.; Xuei, Xiaoling; Chan, Grace; Kang, S.; Manz, N.; Rangaswamy, M.; Rohrbaugh, J.; Wang, J. C.; Brooks, A.; Aliev, F.; Parsian, A.; Reilly, M.

In: PLoS One, Vol. 10, No. 9, e0137671, 18.09.2015.

Research output: Contribution to journalArticle

Mamdani, M, Williamson, V, McMichael, GO, Blevins, T, Aliev, F, Adkins, A, Hack, L, Bigdeli, T, Van Der Vaart, AD, Web, BT, Bacanu, SA, Kalsi, G, Kendler, KS, Miles, MF, Dick, D, Riley, BP, Dumur, C, Vladimirov, VI, Hesselbrock, V, Edenberg, H, Nurnberger, J, Foroud, T, Kuperman, S, Kramer, J, Porjesz, B, Bierut, L, Goate, A, Rice, J, Bucholz, K, Schuckit, M, Tischfield, J, Almasy, L, Taylor, R, Dick, D, Bauer, L, Koller, D, O'Connor, S, Wetherill, L, Xuei, X, Chan, G, Kang, S, Manz, N, Rangaswamy, M, Rohrbaugh, J, Wang, JC, Brooks, A, Aliev, F, Parsian, A & Reilly, M 2015, 'Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence', PLoS One, vol. 10, no. 9, e0137671. https://doi.org/10.1371/journal.pone.0137671
Mamdani, Mohammed ; Williamson, Vernell ; McMichael, Gowon O. ; Blevins, Tana ; Aliev, Fazil ; Adkins, Amy ; Hack, Laura ; Bigdeli, Tim ; Van Der Vaart, Andrew D. ; Web, Bradley Todd ; Bacanu, Silviu Alin ; Kalsi, Gursharan ; Kendler, Kenneth S. ; Miles, Michael F. ; Dick, Danielle ; Riley, Brien P. ; Dumur, Catherine ; Vladimirov, Vladimir I. ; Hesselbrock, V. ; Edenberg, Howard ; Nurnberger, John ; Foroud, Tatiana ; Kuperman, S. ; Kramer, J. ; Porjesz, B. ; Bierut, L. ; Goate, A. ; Rice, J. ; Bucholz, K. ; Schuckit, M. ; Tischfield, J. ; Almasy, L. ; Taylor, R. ; Dick, D. ; Bauer, L. ; Koller, D. ; O'Connor, Sean ; Wetherill, L. ; Xuei, Xiaoling ; Chan, Grace ; Kang, S. ; Manz, N. ; Rangaswamy, M. ; Rohrbaugh, J. ; Wang, J. C. ; Brooks, A. ; Aliev, F. ; Parsian, A. ; Reilly, M. / Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence. In: PLoS One. 2015 ; Vol. 10, No. 9.
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abstract = "Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.",
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T1 - Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence

AU - Mamdani, Mohammed

AU - Williamson, Vernell

AU - McMichael, Gowon O.

AU - Blevins, Tana

AU - Aliev, Fazil

AU - Adkins, Amy

AU - Hack, Laura

AU - Bigdeli, Tim

AU - Van Der Vaart, Andrew D.

AU - Web, Bradley Todd

AU - Bacanu, Silviu Alin

AU - Kalsi, Gursharan

AU - Kendler, Kenneth S.

AU - Miles, Michael F.

AU - Dick, Danielle

AU - Riley, Brien P.

AU - Dumur, Catherine

AU - Vladimirov, Vladimir I.

AU - Hesselbrock, V.

AU - Edenberg, Howard

AU - Nurnberger, John

AU - Foroud, Tatiana

AU - Kuperman, S.

AU - Kramer, J.

AU - Porjesz, B.

AU - Bierut, L.

AU - Goate, A.

AU - Rice, J.

AU - Bucholz, K.

AU - Schuckit, M.

AU - Tischfield, J.

AU - Almasy, L.

AU - Taylor, R.

AU - Dick, D.

AU - Bauer, L.

AU - Koller, D.

AU - O'Connor, Sean

AU - Wetherill, L.

AU - Xuei, Xiaoling

AU - Chan, Grace

AU - Kang, S.

AU - Manz, N.

AU - Rangaswamy, M.

AU - Rohrbaugh, J.

AU - Wang, J. C.

AU - Brooks, A.

AU - Aliev, F.

AU - Parsian, A.

AU - Reilly, M.

PY - 2015/9/18

Y1 - 2015/9/18

N2 - Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

AB - Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

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